Narcolepsy is a sleep disorder affecting 0.05-0.10% of the North American population. Our objective is to dissect the neurochemical control of sleep in narcolepsy using a pharmacological approach and to apply this knowledge to improve the treatment of human narcolepsy.This will also provide critical information on the neurochemical mechanisms generating normal sleep. Our research is facilitated by the use of a canine model of narcolepsy in which the condition is transmitted as a fully penetrant autosomal recessive trait. This proposal is a competitive renewal of an RO1 grant that was originally funded in 1989. We have focused on the pharmacological control of canine cataplexy, a pathological manifestation of REM sleep atonia, and one of the most disabling symptoms of human narcolepsy. Our results indicate that this symptom, similar to REM sleep, is mainly controlled by cholinergic and monoaminergic systems. We have farther identified several receptor subtypes that mediate this neuropharmacological control: muscarinic M2, adrenergic alpha-1b and alpha-2/D2 receptor subtypes. Preliminary experiments also suggest that heterozygous animals have an intermediary phenotype between narcoleptic and control animals. Two-thirds of heterozygous dogs, but never any control dogs, display cataplectic attacks under specific pharmacological conditions where cholinergic transmission is stimulated and monoaminergic transmission is depressed. Sleep recording experiments using narcoleptic, heterozygous and control Dobermans have also demonstrated that narcoleptic dogs are significantly sleepier than controls during the daytime, the few heterozygous animals tested being intermediary. In the next period of funding, we will: (1) apply the knowledge obtained from our pharmacological experiments on canines to improve the treatment of human cataplexy; (2) further characterize the phenotype of homozygous narcoleptic and heterozygous carrier Dobermans. (3) test the hypothesis that the alerting effects of amphetamine-like stimulants are mediated via presynaptic stimulation of dopaminergic transmission. To test this hypothesis, we will attempt to correlate in vivo effects on sleep, in vitro binding affinities for dopamine transporter sites and in vitro dopamine uptake inhibition potency of various stimulants. (4) determine where stimulant compounds act to induce alertness. This will involve local drug injection and in vivo microdialysis experiments. As our preliminary results suggest the involvement of mesolimbic or mesocortical dopaminergic systems in narcolepsy, we will principally focus on these neuroanatomical systems. (5) study the mode of action and the efficacy of other less known classes of stimulants (TRH, histaminergic, adenosinergic, benzodiazepinergic, and alpha-1 compounds). This proposal will enhance our understanding of the pathophysiology of narcolepsy and of the mode of action of stimulant compounds. It should also provide new directions for the development of non-addictive stimulant compounds with higher efficacy.